Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is more or less completely lost. About 2% of all people suffer from diabetes.
Since the discovery of insulin in the 1920's, continuous strides have been made to improve the treatment of diabetes mellitus. To help avoid extreme glucose levels, diabetic patients often practice insulin replacement therapy, whereby insulin is administered by injection.
In the treatment of diabetes mellitus, many varieties of insulin compositions have been suggested and used, including regular insulin, Semilente.RTM. insulin, isophane insulin, insulin zinc suspensions, protamine zinc insulin, and Ultralente.RTM. insulin. As diabetic patients typically are treated with insulin for several decades, there is a major need for safe and life quality improving insulin compositions. Some of the commercially available insulin compositions are characterized by a fast onset of action, while other compositions have a relatively slow onset but show a more or less prolonged action. Fast acting insulin compositions are usually solutions of insulin, while retarded acting insulin compositions can be suspensions containing insulin in crystalline and/or amorphous form precipitated by addition of zinc salts alone or by addition of protamine or by a combination of both. In addition, some patients use compositions having both a fast onset of action and a more prolonged action. Such a composition may be an insulin solution wherein protamine insulin crystals are suspended. Some patients prepare the final composition themselves by mixing an insulin solution with a suspension composition in the desired ratio.
Human insulin consists of two polypeptide chains, the so-called A and B chains, which contain 21 and 30 amino acid residues, respectively. The A and B chains are interconnected by two cystine disulphide bridges. Insulin from most other species has a similar construction, but may not contain the same amino acid residues at corresponding positions.
The development of genetic engineering has made it possible to easily prepare a great variety of insulin compounds analogous to human insulin. In these insulin analogues, one or more of the amino acid residues have been substituted with other amino acid residues which can be coded for by the nucleotide sequences. Since human insulin, as explained above, contains 51 amino acid residues, it is obvious that a large number of insulin analogues is possible, and a great variety of analogues with interesting properties have been prepared. In human insulin solutions with a concentration of interest for injectable compositions, the insulin molecule is present in associated form as a hexamer (Brange et al. Diabetes Care 13, (1990), 923-954). After subcutaneous injection, it is believed that the rate of absorption by the blood stream is dependent on the size of the molecule, and it has been found that insulin analogues with amino acid residue substitutions which counteract or inhibit this hexamer formation have an unusually fast onset of action (Brange et al.: Ibid). This can be of great therapeutic value for the diabetic patient.
A general survey of pharmaceutical compositions containing insulin is given by Brange et al. in Galenics of Insulin, Springer-Verlag (Berlin, 1987).
Pharmaceutical compositions which are based on analogues of human insulin have e.g. been presented by Heinemann et al., Lutterman et al. and Wiefels et al. at the "Frontiers in Insulin Pharmacology" International Symposium in Hamburg, 1992.
U.S. Pat. No. 5,474,978 discloses a rapidly acting parenteral formulation comprising a human insulin analogue hexamer complex consisting of six monomeric insulin analogues, zinc ions and at least three molecules of a phenolic derivative.
Normally, insulin compositions are administered by subcutaneous injection. What is important for the patient is the profile of action of the insulin composition, i.e. the action of insulin on the glucose metabolism as a function of the time from the injection, including the time for the onset of insulin action, the maximum value and the total duration of action. A variety of insulin compositions with different profiles of action are required by patients. An individual patient may thus on the same day use insulin compositions with very different profiles of action. The profile of action required for any given patient at any given time depends upon several factors, e.g. the time of the day and the amount and composition of any meal eaten by the patient.
Also important for the patient is the chemical stability of the insulin compositions, especially due to the abundant use of pen-like injection devices such as devices which contain Penfill.RTM. cartridges, in which an insulin composition is stored until the entire cartridge is empty. This may last 1 to 2 weeks or more for devices containing a 1.5 or 3.0 ml cartridge. During storage, covalent chemical changes in the insulin structure occur. This may lead to the formation of molecules which are less active and potentially immunogenic such as deamidation products and higher molecular weight transformation products (dimers, polymers, etc.). A comprehensive study on the chemical stability of insulin is given in by Jens Brange in "Stability of Insulin", Kluwer Academic Publishers, 1994.
Compositions comprising insulin and insulin analogues are traditionally formulated using various additives, for example sodium phosphate (buffer), Zn.sup.2+ (stabilizer), phenol/m-cresol (preservative and stabilizer), sodium chloride (tonicity agent and stabilizer), and glycerol/mannitol (tonicity agents).
The shelf-life of insulin products is mainly compromised by the formation of soluble aggregates (dimers and polymers) over time, despite the fact that insulin is typically stored at a low temperature of no more than about 5.degree. C., which improves the shelf-life considerably compared to storage e.g. at room temperature. In addition, insulin products are subject to the formation of insoluble aggregates (fibrils) as a result of shaking, e.g. when carried in the pocket of a patient or during transport. It is essential for the quality of an insulin product that the tendency to form such soluble and insoluble aggregates as a result of chemical or physical influences is reduced to an absolute minimum.
Although progress has been made in the chemical and physical stabilization of insulin-containing compositions, the need still remains for improving the shelf-life of such products as well as their in-use time at temperatures of about 20-37.degree. C., i.e. from room temperature to body temperature.
Acta Pharmaceutica Nordica 4(4), 1992, pp. 149-158 discloses insulin compositions with a sodium chloride concentration in the range of 0 to 250 mM. The major part of the compositions, including those which additionally comprise glycerol, contain a rather high amount of sodium chloride, i.e. 0.7%, corresponding approximately to a concentration of 120 mM.
PCT/DK97/00268 (Novo Nordisk A/S) discloses insulin compositions having improved chemical stability, the compositions comprising a combination of glycerol and/or mannitol and 5-100 mM of a halogenide, e.g. sodium chloride.
Storm & Dunn ("The Glu(B13) carboxylates of the insulin hexamer form a cage for Cd.sup.2+ and Ca.sup.2+ ions", Biochemistry 1985, 24, 1749-1756) performed studies showing that the highly co-operative zinc-insulin hexamer (In).sub.6 (Zn.sup.2+).sub.2 is further modulated by calcium binding, because the six Glu-(B13) residues within the hexamer structure form a cage that binds calcium and cadmium ions. The single binding site is stated to bind Ca.sup.2+ and Cd.sup.2+ with high affinity and to be specific for these two ions.